The role of CBL family ubiquitin ligases in cancer progression and therapeutic strategies.

The CBL (Casitas B-lineage lymphoma) family, as a class of ubiquitin ligases, can regulate signal transduction and activate receptor tyrosine kinases through various tyrosine kinase-dependent pathways. There are three members of the family: c-CBL, CBL-b, and CBL-c. Numerous studies have demonstrated the important role of CBL in various cellular pathways, particularly those involved in the occurrence and progression of cancer, hematopoietic development, and regulation of T cell receptors. Therefore, the purpose of this review is to comprehensively summarize the function and regulatory role of CBL family proteins in different human tumors, as well as the progress of drug research targeting CBL family, so as to provide a broader clinical measurement strategy for the treatment of tumors.

Identification of pancreatic adenocarcinoma immune subtype associated with tumor neoantigen from aberrant alternative splicing.

Background: Pancreatic adenocarcinoma (PAAD) is referred to as an immunologically "cold" tumor that responds poorly to immunotherapy. A fundamental theory that explains the low immunogenicity of PAAD is the dramatically low tumor mutation burden (TMB) of PAAD tumors, which fails to induce sufficient immune response. Alternative splicing of pre-mRNA, which could alter the proteomic diversity of many cancers, has been reported to be involved in neoantigen production. Therefore, we aim to identify novel PAAD antigens and immune subtypes through systematic bioinformatics research. Methods: Data for splicing analysis were downloaded from The Cancer Genome Atlas (TCGA) SpliceSeq database. Among the available algorithms, we chose CIBERSORT to evaluate the immune cell distribution among PAADs. The TCGA-PAAD expression matrix was used to construct a co-expression network. Single-cell analysis was performed based on the Seurat workflow. Results: Integrated analysis of aberrantly upregulated genes, alternatively spliced genes, genes associated with nonsense-mediated RNA decay (NMD) factors, antigen presentation and overall survival (OS) in TCGA-PAAD revealed that PLEC is a promising neoantigen for PAAD-targeted therapy. We identified a C2 TCGA-PAAD subtype that had better prognosis and more CD8+ T-cell infiltration. We propose a novel immune subtyping system for PAAD to indicate patient prognosis and opportunities for immunotherapy, such as immune checkpoint (ICP) inhibitors. Conclusions: In conclusion, the present study used a transcriptome-guided approach to screen neoantigen candidates based on alternative splicing, NMD factors, and antigen-presenting signatures for PAAD. A prognosis model with guidance of immunotherapy will aid in patient selection for appropriate treatment.

Discovery of piperine derivatives as inhibitors of human dihydroorotate dehydrogenase to induce ferroptosis in cancer cells.

Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development.

Promotion of stem cell-like phenotype of lung adenocarcinoma by FAM83A via stabilization of ErbB2.

Lung cancer stands as the leading cause of mortality among all types of tumors, with over 40% of cases being lung adenocarcinoma (LUAD). Family with sequence similarity 83 member A (FAM83A) emerges as a notable focus due to its frequent overexpression in LUAD. Despite this, the precise role of FAM83A remains elusive. This study addresses this gap by unveiling the crucial involvement of FAM83A in maintaining the cancer stem cell-like (CSC-like) phenotype of LUAD. Through a global proteomics analysis, the study identifies human epidermal growth factor receptor 2 (HER2 or ErbB2) as a crucial target of FAM83A. Mechanistically, FAM83A facilitated ErbB2 expression at the posttranslational modification level via the E3 ubiquitin ligase STUB1 (STIP1-homologous U-Box containing protein 1). More importantly, the interaction between FAM83A and ErbB2 at Arg241 promotes calcineurin (CALN)-mediated dephosphorylation of ErbB2, followed by inhibition of STUB1-mediated ubiquitin-proteasomal ErbB2 degradation. The maintenance of the CSC-like phenotype by FAM83A, achieved through the posttranslational regulation of ErbB2, offers valuable insights for identifying potential therapeutic targets for LUAD.

Revealing molecular and cellular heterogeneity in hypopharyngeal carcinogenesis through single-cell RNA and TCR/BCR sequencing.

Introduction: Hypopharyngeal squamous cell carcinoma (HSCC) is one of the malignant tumors with the worst prognosis in head and neck cancers. The transformation from normal tissue through low-grade and high-grade intraepithelial neoplasia to cancerous tissue in HSCC is typically viewed as a progressive pathological sequence typical of tumorigenesis. Nonetheless, the alterations in diverse cell clusters within the tissue microenvironment (TME) throughout tumorigenesis and their impact on the development of HSCC are yet to be fully understood. Methods: We employed single-cell RNA sequencing and TCR/BCR sequencing to sequence 60,854 cells from nine tissue samples representing different stages during the progression of HSCC. This allowed us to construct dynamic transcriptomic maps of cells in diverse TME across various disease stages, and experimentally validated the key molecules within it. Results: We delineated the heterogeneity among tumor cells, immune cells (including T cells, B cells, and myeloid cells), and stromal cells (such as fibroblasts and endothelial cells) during the tumorigenesis of HSCC. We uncovered the alterations in function and state of distinct cell clusters at different stages of tumor development and identified specific clusters closely associated with the tumorigenesis of HSCC. Consequently, we discovered molecules like MAGEA3 and MMP3, pivotal for the diagnosis and treatment of HSCC. Discussion: Our research sheds light on the dynamic alterations within the TME during the tumorigenesis of HSCC, which will help to understand its mechanism of canceration, identify early diagnostic markers, and discover new therapeutic targets.

Hadamard ghost imaging with a small amount of mask plates based on a spread spectrum.

Ghost imaging techniques using low-cost bucket detectors have unrivaled advantages for some wavebands where plane array detectors are not available or where focusing is difficult. In these bands, fine mask plates are the key to implementing high-resolution and quality ghost imaging. However, manufacturing a large number of mask plates is necessary but undoubtedly expensive in traditional Hadamard ghost imaging (HGI). Inspired by the spread spectrum technology, Hadamard ghost imaging based on spread spectrum (HGI-SS) is proposed, in which only two sets of a small number of mask plates are needed to accomplish Nyquist sampling for the object. Their numbers are equal to the lateral pixel resolution and the vertical pixel resolution of the object, respectively. Optical experiments verify the effectiveness of the scheme. For ghost imaging with a resolution requirement of 128 × 128 pixels, HGI-SS needs to prepare only 256 mask plates, while the traditional HGI needs to prepare 16,384 mask plates. HGI-SS may be helpful to expand the pixel resolution of imaging at a relatively low cost of mask plates.

Rapid detection of furanyl fentanyl in complex matrices using Leidenfrost desorption-assisted low-temperature arc plasma ionization mass spectrometry.

The abuse of illicit drugs poses serious threats to the physical and mental health of users, as well as to the overall safety and welfare of society. In this work, we present a newly developed technique for drug detection based on mass spectrometry. This technique combines Leidenfrost desorption with low-temperature arc plasma ionization mass spectrometry. This method is applicable for detecting furanyl fentanyl in complex matrices. Key advantages of this technique include minimal sample fragmentation and high sensitivity for detection. The Leidenfrost desorption plays a pivotal role in this methodology, as it spontaneously concentrates analyte molecules during the gradual evaporation of the solvent. Eventually, these concentrated molecules are redistributed at their highest concentrations, resulting in exceptionally high sensitivity. In the course of our investigation, we achieved a remarkable detection limit of 10 pg mL-1 for furanyl fentanyl in pure water. Moreover, the characteristic ion peaks of furanyl fentanyl can be distinctly identified within complex matrices such as wine, beverages, urine, and lake water. This innovative drug detection technology offers several advantages, including a simple setup, cost-effectiveness, rapid detection, high sensitivity, and minimal sample pretreatment.

Tensor-Free Holographic Metasurface Leaky-Wave Multi-Beam Antennas with Tailorable Gain and Polarization.

Recently, the community has seen a rise in interest and development regarding holographic antennas. The planar hologram is made of subwavelength metal patches printed on a grounded dielectric board, constituting flat metasurfaces. When a known reference wave is launched, the hologram produces a pencil beam towards a prescribed direction. Most earlier works on such antennas have considered only a single beam. For the few later ones that studied multiple beams, they were achieved either by having each beam taken care of by a distinct frequency or by partitioning the hologram, thereby depriving each beam of the directivity it could have had it not shared the holographic aperture with other beams. There have been recent studies related to the use of tensor surface impedance concepts for the synthesis of holograms which have attained control over the polarizations and intensities of the beams. However, this approach is complicated, tedious, and time-consuming. In this paper, we present a method for designing a planar holographic leaky-wave multi-beam metasurface antenna, of which each simultaneous beam radiating at the same frequency towards any designated direction has a tailorable amplitude, phase, and polarization, all without hologram partitioning. Most importantly, this antenna is exempted from the need for the cumbersome technique of tensor impedance. Such features of beam configurability are useful in selective multiple-target applications that require differential gain and polarization control among the various beams. Only a single source is needed, which is another benefit. In addition, effective methods to mitigate sidelobes are also proposed here. Designs by simulations according to the method are herein validated with measurements performed on fabricated prototypes.

Can a "Pandemic Life Adaptation" Digital Technology Curriculum Reduce the Digital Disadvantage of Older Adults During COVID-19? An Intervention Study from Shanghai.

Older adults are at a digital disadvantage because of social stereotypes and a lack of social support; however, smartphones have become a necessary technology to cope with crises and daily life in China, especially during the pandemic. This study aimed to help marginalized older adults take on new tasks by developing digital technology education that used a framework of social cognitive theory in social work. The study followed a quasi-experimental design in which 153 elderly people were recruited from three community service centers; 90 of the participants received 6-weekly intervention. Intent-to-treat analysis, effect size calculations, and sensitivity analysis were conducted. The findings show that digital education significantly enhanced two domains of digital life adaptation abilities: general digital life adaptation abilities [g = .50, 95% CI (.70, 2.69)] and pandemic digital life adaptation abilities [g = .89, 95% CI (.96, 2.07)]. The intervention also improved three domains of digital self-efficacy: sharing and communication [g = .55, 95% CI (.04, .48)], verification [g = .34, 95% CI (.01, .59)], and influencing others [g = .53, 95% CI (.13, .77)]. The study showed that the new intervention approach reduced the harm to vulnerable older adults in the digital wave, especially during the pandemic.

EFFECTS OF LEVOSIMENDAN ON DIAPHRAGMATIC DYSFUNCTION IN PATIENTS WITH SEPSIS.

ABSTRACT: Objective: In this study, our aim was to examine the effects of levosimendan on diaphragmatic dysfunction in patients with sepsis, as well as assess its impact on respiratory muscle contractility and the outcome of weaning. Methods: This was a single-blind, randomized, controlled trial. Patients with diaphragmatic dysfunction and failure of spontaneous breathing trials (SBTs) were randomly and equally assigned to the experimental and control groups. The experimental group received levosimendan at a loading dose of 6 µg/kg for 10 min, followed by a continuous infusion at 0.2 µg/kg/min. The control group received an equivalent dose of a placebo. The preadministration and postadministration respiratory mechanics parameters of the patients were recorded. Evaluation of the effect of levosimendan on patients with sepsis-induced diaphragm dysfunction comprised arterial blood gas analysis as well as ultrasound measurements of diaphragm excursion (DE), diaphragm thickness (DT), diaphragm thickening fraction (TFdi), and diaphragm-rapid shallow breathing index (D-RSBI). Results: Forty-four patients were enrolled in the study. We found that postadministration of levosimendan, the patients' tidal volume (GCSMV) increased, whereas the D-RSBI decreased, and the partial pressure of carbon dioxide (PACO 2 ) decreased when compared to the preadministration levels. Additionally, following levosimendan administration, patients showed increased DE and pressure support (PS) when compared to before administration (1.14 ± 0.177 vs. 1.22 ± 0.170 cm and 0.248 ± 0.03 vs. 0.284 ± 0.06, respectively) and decreased D-RSBI (22.76 ± 6.14 vs. 20.06 ± 6.04, respectively), all of which were statistically significant ( P < 0.05). In contrast, in the control group of patients, there were no statistically significant differences in the postadministration levels of DE, TFdi, and D-RSBI as compared to the preadministration period ( P > 0.05). Furthermore, in terms of weaning outcomes, we did not find any statistically significant difference in the number of patients in the two groups who eventually underwent weaning ( P = 0.545). Conclusion: In this study, we found that levosimendan enhanced diaphragm contractile function. However, further investigations are required to explore its effect on weaning outcomes in patients undergoing mechanical ventilation.

Tissue-Resident Alveolar Macrophages Reduce Ozone-induced Inflammation via MerTK-mediated Efferocytosis.

Lung inflammation, caused by acute exposure to ozone (O3), one of the six criteria air pollutants, is a significant source of morbidity in susceptible individuals. Alveolar macrophages (AMØs) are the most abundant immune cells in the normal lung, and their number increases after O3 exposure. However, the role of AMØs in promoting or limiting O3-induced lung inflammation has not been clearly defined. In this study, we used a mouse model of acute O3 exposure, lineage tracing, genetic knockouts, and data from O3-exposed human volunteers to define the role and ontogeny of AMØs during acute O3 exposure. Lineage-tracing experiments showed that 12, 24, and 72 hours after exposure to O3 (2 ppm) for 3 hours, all AMØs were of tissue-resident origin. Similarly, in humans exposed to filtered air and O3 (200 ppb) for 135 minutes, we did not observe at ∼21 hours postexposure an increase in monocyte-derived AMØs by flow cytometry. Highlighting a role for tissue-resident AMØs, we demonstrate that depletion of tissue-resident AMØs with clodronate-loaded liposomes led to persistence of neutrophils in the alveolar space after O3 exposure, suggesting that impaired neutrophil clearance (i.e., efferocytosis) leads to prolonged lung inflammation. Moreover, depletion of tissue-resident AMØs demonstrated reduced clearance of intratracheally instilled apoptotic Jurkat cells, consistent with reduced efferocytosis. Genetic ablation of MerTK (MER proto-oncogene, tyrosine kinase), a key receptor involved in efferocytosis, also resulted in impaired clearance of apoptotic neutrophils after O3 exposure. Overall, these findings underscore the pivotal role of tissue-resident AMØs in resolving O3-induced inflammation via MerTK-mediated efferocytosis.

New indolequinazoline alkaloids from the fruits of Tetradium ruticarpum.

In this research, five new indolequinazoline alkaloids (1-5), along with six known indolequinazoline alkaloids (6-11) were obtained from the fruits of Tetradium ruticarpum. Their structures were elucidated through comprehensive spectroscopic data of 1D and 2D NMR, HRESIMS and ECD spectra. Additionally, all isolates were assayed for their SIRT1 inhibitory activities in vitro and compounds 2, 7, 10 and 11 exhibited activities with IC50 values ranged from 43.16 to 118.35 µM.

Withanolides from Physalis angulata var. villosa and the Relative Configurational Revision of Some Known Analogs.

Physalis angulata var. villosa is a plant possessing abundant withanolides, but in-depth research is lacking. In our ongoing study of P. angulata var. villosa, 15 previously undescribed withanolides (1-15), along with 21 known analogs (16-36), were isolated from the whole plant. The structures of the withanolides (1-15) were elucidated based on analysis of their 1D and 2D NMR, HRESIMS, and ECD data. Additionally, the application of γ-gauche effects with the help of ROESY correlations led to the formulation of empirical rules for withanolides with 14-OH/15-OAc to rapidly determine the 14-OH orientations, making it possible to propose configurational revisions of 19 previously reported analogs (1'-19'). Withanolides 1, 4-6, and 10 showed potent cytotoxic activities against three human cancer cell lines (HCT-116, MDA-MB-231, and A549).

Prediction of fluid responsiveness for patients in shock using a ventilator disconnection test combined with the pulse contour-derived cardiac index.

BACKGROUND: Finding a simple and reliable method to predict and assess fluid responsiveness has long been of clinical interest. OBJECTIVE: To investigate the predictive value of a ventilator disconnection (DV) test combined with the pulse contour-derived cardiac output (PiCCO) index on fluid responsiveness for patients in shock. METHODS: Thirty-two patients were chosen for the study. Patients who were in shock, received mechanical ventilation, and met the inclusion criteria were selected. Patients were divided into a fluid-responsive group (14 patients) and fluid-unresponsive group (18 patients) based on whether the increase in cardiac index (Δ CI) was > 10% or not, respectively, following the fluid challenge test. Changes in heart rate, pulse oximeter-measured oxygen saturation, mean arterial pressure (MAP), and CI before and after passive leg raising (PLR), DV, and fluid challenge tests were observed. We used Pearson's correlation coefficient to analyze an increase in the MAP (Δ MAP) and Δ CI before and after the PLR, DV, and fluid challenge tests; the sensitivity and specificity of the Δ MAP and Δ CI in the PLR and DV tests for predicting fluid response were also analyzed by plotting the receiver operating characteristic (ROC) curves. RESULTS: CI results in the PLR and DV tests, as well as the fluid challenge test, were significantly higher in the fluid-responsive group compared with before the test (P< 0.05). The Δ CI before and after the PLR, DV, and fluid challenge tests were positively correlated among patients in the fluid-responsive group. The area under the ROC curve for the post-PLR test CI and the post-DV CI for predicting fluid responsiveness was 0.869 (95% confidence interval (CI) [0.735-1.000, P= 0.000]) and 0.937 (95% CI [0.829-1.000, P= 0.000]), respectively, in patients in the fluid-responsive group. The sensitivity and specificity of the post-DV CI for predicting fluid responsiveness in all patients was 100.0% and 88.9%, respectively, using a 5% increase as the cut-off value. CONCLUSION: Application of DV, combined with PiCCO, has a high predictive value for fluid responsiveness among patients in shock.

Implicit and explicit measures of loyalty assessment among military cadets / 陆军军医大学学报

Objective To explore the relevant relationship and specificity between the implicit and explicit loyalty of military cadets in order to provide a theoretical basis and objective indicators for a more comprehensive and objective assessment for individual loyalty.Methods E-Prime 2.0,a classic implicit association paradigm was employed to construct an implicit association loyalty test for 64 military cadets.Simultaneously,an explicit loyalty measurement was conducted using the Chinese Military Personnel Loyalty Scale.Results ① Significant implicit effect was observed in the loyalty assessment of military cadets,indicating a general tendency to perceive higher levels of personal loyalty and lower levels of loyalty to external entities.② Explicit loyalty assessment revealed that the participants had the highest loyalty score towards the Party,the Nation,and the People(4.79±0.34),followed by the loyalty score to their profession(4.38±0.53),and the relatively lower loyalty score towards the unit and leaders(4.03±0.83).Among the 3 dimensions of loyalty,the normative loyalty score ranked highest,while continuance loyalty score took lower.③ There were no correlations among the scores of loyalty to the Party,the Nation,and the People(r=-0.030,P=0.823),to the profession(r=-0.047,P=0.728),to the unit(r=0.050,P=0.710),or to the leaders(r=0.043,P=0.749).Conclusion The implicit effect in the loyalty assessment is significant in military cadets,and there is no significant correlation between explicit and implicit loyalty measurements.Thus,we cannot rely solely on explicit measurements to assess their loyalty attitudes.

Nurses' Work-Family Strategies during COVID-19 Lockdown and Their Association with Individual Health and Family Relations.

The COVID-19 lockdown forced people to stay at home and address their family duties more equally. However, since nurses themselves were involved in the closed-loop management in hospitals and unable to return home, there was also an increased likelihood of non-traditional work-family strategies emerging. To ascertain the extant and implications of this phenomenon, this cross-sectional study explores work-family management strategies among nurses during the COVID-19 lockdown and their association with nurses' individual health, family relationships, and job performance. Survey data were collected from 287 nurses who were involved in the closed-loop management in Shanghai hospitals from March to June 2022. Latent Class Analysis of seven categorical variables of nurses' work-family status (e.g., the division of childcare labor) produced a best-fit solution of five strategies (BLRT (p) < 0.001, LMR (p) = 0.79, AIC = 5611.34, BIC = 6302.39, SSA-BIC = 5703.65, Entropy = 0.938): (1) fully outsourcing to grandparents, (2) partially outsourcing to grandparents, with the husband filling in the gap, (3) the husband does it all, (4) egalitarian remote workers, and (5) a neo-traditional strategy. Nurses who applied the egalitarian strategy had less psychological distress and relationship tension and better performance than those who applied the neo-traditional strategy and performed most of the childcare. The "husband does it all" strategy and the outsourcing strategies seem to have double-edged effects, with better job performance and family relations but also more distress and fewer sleeping hours among nurses. Overall, with a view to future risk mitigation, policymakers and practitioners should be aware of the diversity of the work-family strategies among nurse families during the lockdown period, and their association with individual and family outcomes, and provide tailored support.

Optical authentication method based on correspondence ghost imaging.

Ghost imaging technology has a great application potential in optical security because of its non-local characteristics. In this paper, on the basis of computational ghost imaging, an optical authentication scheme is proposed that utilizes the correspondence imaging technique for the preliminary reconstruction of the object image, and then authenticates the image by a nonlinear correlation algorithm. Different from the previous optical authentication schemes that usually adopted random selection of measurements, this authentication method consciously selects the bucket detector measurement values with large fluctuation and can achieve authentication using ultra-low data volumes less than 1% of the Nyquist limit. In brief, this scheme is easy to implement and has a simpler algorithm and higher stability, which is a tremendous advantage in practical optical authentication systems. The simulation and physical experimental results demonstrate the feasibility of the scheme.

MSA-GCN: A Multi-information Selection Aggregation Graph Convolutional Network for Breast Tumor Grading.

Physicians typically combine multi-modal data to make a graded diagnosis of breast tumors. However, most existing breast tumor grading methods rely solely on image information, resulting in limited accuracy in grading. This paper proposes a Multi-information Selection Aggregation Graph Convolutional Networks (MSA-GCN) for breast tumor grading. Firstly, to fully utilize phenotypic data reflecting the clinical and pathological characteristics of tumors, an automatic combination screening and weight encoder is proposed for phenotypic data, which can construct a population graph with improved structural information. Then, a graph structure is designed through similarity learning to reflect the correlation between patient image features. Finally, a multi-information selection aggregation mechanism is employed in the graph convolution model to extract the effective features of multi-modal data and enhance the classification performance of the model. The proposed method is evaluated on different clinical datasets from the Digital Database for Screening Mammography (DDSM) and INbreast. The average classification accuracies are 90.74% and 85.35%, respectively, surpassing the performance of existing methods. In conclusion, our method effectively fuses image and non-image information, leading to a significant improvement in the accuracy of breast tumor grading.

Discovery and optimization of indirubin derivatives as novel ferroptosis inducers for the treatment of colon cancer.

Glutathione peroxidase 4 (GPX4) is an essential antioxidant enzyme that negatively regulates ferroptosis. To exploit novel GPX4 inhibitors, we designed and synthesized 32 indirubin derivatives. Compound 31 exhibited the strongest antitumor activity against HCT-116 cells (IC50 = 0.49 ± 0.02 µM). Further studies suggested that 31 could induce ferroptosis in colon cancer cells and its cytotoxic activity could be reversed by ferroptosis inhibitors. Mechanism research showed that 31 promoted the degradation of GPX4, causing the accumulation of lipid ROS to induce ferroptosis. Animal experiments also proved that 31 could inhibit the growth of colon cancer cells in vivo and reduce the expression of GPX4 in tumor tissues. These results indicated that compound 31 had potential as a novel ferroptosis inducer agent for colon cancer.